Cardiogenetics in Action

Thomas V. McDonald, M.D., Professor of medicine (cardiology) and of molecular pharmacologyMany individualized diagnostics and therapeutics have already found their way into everyday clinical practice. The recent case of Adam (not his real name), a young boy who was treated at The Children’s Hospital at Montefiore, is a perfect example.

After fainting several times, Adam was diagnosed with long QT syndrome, a type of arrhythmia that can cause fast, chaotic heartbeats, with potentially fatal consequences. In the past, the boy would probably have been given the standard anti-arrhythmia therapy, a beta blocker. His doctors might also have recommended an implantable cardiodefibrillator (ICD), a small device that can instantly detect and correct abnormal heart rhythms.

Since implanting an ICD requires surgery and carries some risks, it is usually reserved for patients with dangerous arrhythmias or a lethal family history of the disease. But Adam was adopted and his family’s history was unknown, so the risk-benefit ratio of implanting an ICD was difficult to assess. Fortunately, Adam’s Montefiore doctors were able to find exactly what therapies he needed, no more and no less.

“We now know many of the genetic mutations that can cause long QT,” explains one of his caregivers, Thomas V. McDonald, M.D., professor of medicine (cardiology) and of molecular pharmacology at Einstein, attending cardiologist at Montefiore and co-director of the Einstein-Montefiore Cardiogenetics Clinic. “So, as a matter of routine, we sent a sample of Adam’s DNA to the lab for genetic testing.”

The test revealed a genetic variant never before seen—a result that would put most cardiologists back at square one. But Dr. McDonald’s lab was equipped to delve deeper into Adam’s DNA anomalies using sophisticated genetic sleuthing. Then his team recreated that mutation in a cellular model and determined its physiological effect.

“We found that Adam’s mutation wasn’t a severely deleterious variant, so an ICD wasn’t necessary,” he says. “We were able to reassure his family that he has little risk of sudden cardiac death."

What’s more, Dr. McDonald was able to recommend appropriate treatment for Adam’s particular arrhythmia risk. All genetic mutations that cause long QT do so by disturbing ion channels in the heart. However, the various mutations affect different channels in different ways and thus require different remedies.

“In Adam’s case, the genetic variation caused a gain of function in his heart’s potassium channels, which is best treated with beta blockers,” says Dr. McDonald, a basic researcher as well as a clinician. “If, on the other hand, his potassium channels were underactive, we would be looking at different drugs.”